COX-1 and COX-2 are two enzymes that convert arachidonic acid into prostaglandin H2. In mammals, different tissues express varying levels of COX-1 and COX-2. COX-1 is a constitutive enzyme found in most mammalian cells. COX-2 is an inducible enzyme expressed at low levels in most healthy tissues, but stimulated during inflammation. Both COX-1 and COX-2 are inhibited by compounds belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs), which include aspirin and indomethacin. COX-2 is selectively inhibited by the so-called coxibs, which include celecoxib and rofecoxib.
Both non-selective COX-1/COX-2 inhibitors and COX-2-selective inhibitors exert serious side effects when administered to humans. COX-1 inhibition has been correlated to peptic ulcerations, dyspepsia and kidney disease, while selective COX-2 inhibition has been correlated to increased cardiovascular risk.
FAAH is an intracellular serine hydrolase responsible for the deactivating hydrolysis of a family of naturally occurring fatty-acid ethanolamides (FAEs), which include endogenous agonists at cannabinoid receptors, such as anandamide, and at peroxisome proliferator-activated receptor-alpha (PPAR-α), such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Two isoforms of FAAH exist, called FAAH-1 and FAAH-2. Both isoforms are generically referred to here as FAAH. Pharmacological inhibition of FAAH activity magnifies and prolongs the biological actions of these lipid-derived messengers, offering a potential strategy to treat pathological conditions such as pain and inflammation.
Inflammatory pathologies afflict hundreds of millions of people worldwide. Yet the use of current therapies is limited by potentially serious side effects, such as gastric damage, kidney damage and increased risk of stroke.
Therefore, a need still exists for new therapeutically active compounds, which are effective in the treatment of inflammation and related conditions whose administration results in a reduced risk of side effects in humans.
One of the objects of the present invention is to provide compounds acting as combined inhibitors of FAAH, COX-1 and/or COX-2. These compounds are effective in the treatment of conditions where the regulation of these enzymes is desirable.